An unexpected discovery at UVA Cancer Center has allowed scientists to halt
the development of small-cell lung cancer in lab mice, and the surprise
finding could open the door to a new treatment approach in people.
The researchers, led by UVA’s Kwon-Sik Park, PhD, and John H. Bushweller,
PhD, were seeking to understand the role of a mutation in the EP300 gene in
the formation of small-cell lung cancer tumors. Their experiments revealed
that the gene makes a protein with surprising properties that can both
foster or prevent the development of small-cell lung cancer. By preventing
the gene from acting as a tumor-promoter, the researchers were able to stop
the cancer from forming and spreading. This held true in both cell samples
and lab mice.
The protein’s essential role in tumor formation makes it an enticing target
for researchers seeking to development new treatments for small-cell lung
cancer (SCLC), an exceptionally dangerous form of cancer. Overall five-year
survival for patients diagnosed with SCLC is only about 7%.
“The most remarkable aspect of our findings is that we explained the unique
vulnerability of EP300 at the molecular level, down to a single amino acid,”
said Park, of the School of Medicine’s Department of Microbiology,
Immunology and Cancer Biology. “Given the frequent EP300 mutations found in
a wide range of cancer types, I hope that the concept of targeting the EP300
KIX domain will have a more general applicability for cancer therapy.”
About Small-Cell Lung Cancer
Small-cell lung cancer is responsible for approximately 13% of lung cancer
diagnoses. Patients typically have better outcomes when it is caught early,
before it has spread outside the lung, but it is a fast-growing cancer and
is often discovered after it has already spread. Smoking is a major risk
factor. Current treatment options include surgery, chemotherapy, radiation
and immunotherapy, but, for most patients, treatments do not cure the
cancer. That means better options are urgently needed.
UVA’s new findings point to a potential new approach. Park and his team made
their surprise discovery while investigating the role of the EP300 gene in
the development of SCLC using genetically engineered mouse models.
Remarkably, they found the protein the gene makes could both promote and
suppress tumor formation. One component, or “domain,” of the protein
appeared to foster cancer development, while another appeared to impede
it.
The scientists further investigated the tumor-promoting domain, called KIX,
and found it was essential for SCLC development. The cancer couldn’t exist
without it. The cancer, it turned out, had to get its KIX.
That suggests that targeting KIX could offer a way to treat SCLC in
patients, the scientists say. In a new scientific paper outlining their
findings, they call KIX a “unique vulnerability” in small-cell lung
cancer.
To explore this newfound vulnerability, Park immediately turned to UVA’s
Bushweller and Tim Bender, PhD, who previously had considered targeting the
KIX domain. A fruitful collaboration instantly ensued.
“Based on this data, we are quite excited to pursue the development of a
drug targeting the KIX domain, as this will likely have multiple
applications for cancer treatment, particularly for SCLC and leukemia,” said
Bushweller, of UVA’s Department of Molecular Physiology and Biological
Physics.
The researchers were pleased that their collaboration has produced such a
promising lead in the effort to develop better therapies for small-cell lung
cancer.
“This study was one of the best examples for the interdisciplinary
collaborations happening at UVA, spearheaded by talented and hardworking
postdocs Kee-Beom Kim and Asish Kabra,” Park noted.
Reference:
Kim KB, Kabra A, Kim DW, et al. KIX domain determines a selective
tumor-promoting role for EP300 and its vulnerability in small cell lung
cancer. Sci. Adv. 2022;8(7):eabl4618.
doi: 10.1126/sciadv.abl4618